In the art, the following methods are known for the production method of optically active azetidine-2-carboxylic acid derivatives.
(1) The method which comprises reacting L-2,4-diaminobutyric acid with hydrochloric acid-nitric acid to prepare a L-4-amino-2-chlorobutyric acid and subjecting the same to heat treatment in an aqueous solution of barium hydroxide to give D-azetidine-2-carboxylic acid [Biochemical. Journal, vol. 64, page 323 (1956)].(2) The method which comprises reacting γ-butyrolactone with bromine in the presence of red phosphorus, treating the reaction product with hydrogen chloride gas-saturated benzyl alcohol to prepare benzyl DL-2,4-dibromobutyrate, reacting the obtained product with benzhydrylamine to prepare benzyl DL-N-diphenylmethylazetidine-2-carboxylate, reducing the reaction product with hydrogen in methanol in the presence of palladium carbon to prepare DL-azetidine-2-carboxylic acid, reacting the obtained product with benzyloxycarbonyl chloride to prepare DL-N-(benzyloxycarbonyl)azetidine-2-carboxylic acid, subjecting the reaction product to optical resolution using L-tyrosine hydrazide to prepare L-N-(benzyloxycarbonyl)-azetidine-2-carboxylic acid and finally reducing the same again with hydrogen in methanol in the presence of palladium carbon to give L-azetidine-2-carboxylic acid [Journal of Heterocyclic Chemistry, vol. 6, pages 435 and 993 (1969)].(3) The method which comprises S-alkylating L-N-(tosyl)methionine to prepare L-N-(tosyl)methionine sulfonium salt, converting the same to L-N-tosyl-α-amino-γ-butyrolactone by heating in an aqueous solution of sodium hydroxide, treating the lactone with a hydrogen halide gas in an alcohol to prepare alkyl L-N-tosyl-2-amino-4-halobutyrate, subjecting the reaction product to ring closure reaction in dimethylformamide with sodium hydride to prepare L-N-(tosyl)azetidine-2-carboxylic acid, and allowing the tosyl group to be eliminated from the reaction product in liquid ammonia using metallic sodium to give L-azetidine-2-carboxylic acid [Chemistry Letters, page 5 (1973)].(4) The method which comprises cyclizing an L-aspartic acid diester to prepare 4-oxo-2-azetidinecarboxylic acid derivative, reducing the same with lithium aluminum hydride to prepare L-azetidine-2-methanol, N-tert-butoxycarbonylating the reaction product to prepare N-(tert-butoxycarbonyl)-azetidine-2-methanol and oxidizing the reaction product to prepare L-N-(tert-butoxycarbonyl) azetidine-2-carboxylic acid, followed by deprotection to give L-azetidine-2-carboxylic acid (WO 9847867).
These methods, however, have problems such as mentioned below.
As for the method (1), L-2,4-diaminobutyric acid is expensive and, for obtaining the more useful L-form of azetidine-2-carboxylic acid, the more expensive D-form of 2,4-diaminobutyric acid is required. In addition, it is necessary to carry out the reaction procedure in the first step more strictly since the reaction temperature, reaction time and other conditions in that step influence the optical purity of the desired compound.
As for the method (2), the process is lengthy and, in addition, benzhydrylamine is expensive. Furthermore, the unrequited optically active substance obtained by optical resolution will be discarded unless an advantageous method of racemization thereof is found and it is economically disadvantageous.
As for the method (3), the process is lengthy and, in addition, the use of metallic sodium in liquid ammonia in the step of tosyl group elimination requires the use of a low-temperature apparatus and needs the caution in handling the same.
As for the method (4), lithium aluminum hydride, which needs caution in handling, is used as a reducing agent of azetidinone and this produces problems in industrialization.
Thus, as an industrial production method, each of the conventional production methods has problems to be solved.
Meanwhile, as methods for preparing optically active N-(alkoxycarbonyl)azetidine-2-carboxylic acids, the method comprising converting a mixture of optical isomers of azetidine-2-carboxylic acid to N-(benzyloxycarbonyl) azetidine-2-carboxylic acid by reacting with benzyloxycarbonyl chloride and optically resolving the resulting product using optically active tyrosine hydrazide (Journal of Heterocyclic Chemistry, page 993 (1969)) and the method comprising optically resolving a mixture of optical isomers of azetidine-2-carboxylic acid using optically active tartaric acid to prepare optically active azetidine-2-carboxylic acid (WO 9702241), followed by tert-butyloxycarbonylating the optical isomer obtained (Heterocylces, page 2539 (1986)) are known in the art.
However, in all of the above methods, it is necessary to use an expensive optically active resolving agent and, in addition, there is a problem that a number of multi-stage steps is required, such as the step of resolving agent separation.
In view of the above-mentioned state of the art, it is an object of the present invention to provide a production method of an optically active azetidine-2-carboxylic acid which method is efficient and economical and can be carried out in an industrially advantageous manner.
Further, in view of the above-mentioned state of the art, it is another object of the invention to provide a method for preparing an optically active N-(alkoxycarbonyl)azetidine-2-carboxylic acid with high optical purity in one stage step from a mixture of optical isomers of the N-(alkoxycarbonyl)-azetidine-2-carboxylic acid, without using any expensive optical resolution agent.